Identify low-penetrance susceptibility genes in a case-control study of breast cancer. The most important category of low-penetrance cancer susceptibility genes is common genetic variants in cancer-related genes. Allele variant genes have been found to increase cancer risk for many different organ sites. The significant role of sex hormones in breast cancer pathogenesis has lead to many investigations of allele variants in genes that regulate steroid hormone metabolism. Recently, a polymorphism in the MnSOD gene has been linked to breast cancer risk and outcome, and a common BRCA2 allele variant was found to be associated with breast cancer in several studies. Our objective is to study a large set of genetic polymorphisms in clusters of genes that regulate four distinct pathways. We have completed the analyses of more than 100 genotypes in candidate genes in collaboration with the NCI Core Genotyping and are exploring genetic susceptibility that is driven by: 1) chronic inflammation, 2) hormone-stimulated survival and proliferation of mutant cells, 3) an impaired DNA repair capacity, and 4) tumor angiogenesis. We will not only analyze genotypes, but also the association of gene haplotypes with breast cancer for several candidate susceptibility genes. For some of the genes, such as MBL2 and NOS2, we have data showing that single genotypes are associated with breast cancer. To address the limitation that the degree of risk conferred by a low-penetrance gene is generally modest and is frequently affected by other genetic variations in genes of the same pathway, we will use PIA to study high-order gene-gene interactions in our study of breast cancer. PIA is a software that can be used to analyze a large set of genotypes in case-control studies to determine which genotype combination is the best predictor of a case status. The software can overcome the limitations of traditional regression models in respect to high-order interactions. PIA has been developed in collaboration with Brian Luke at the NCI Frederick Advanced Biomedical. We established a breast cancer case-control study in the greater Baltimore area. The objectives of this study are to: identify genetic risk factors for breast cancer, investigate the association between allele variant genes and cancer progression, and survival in an African-American and Caucasian population. The study population consists of 293 cases and 317 controls. Study subjects were recruited between 1993 and 2002. Cases had pathologically confirmed breast cancer, and had residency in Baltimore, or surrounding areas. They had, by self-report, no previous history of the disease. The controls were frequency-matched to cases by race and age, and had by self-report, no history of breast cancer. They are either hospital-based (n=230) or population-based (n=87). Hospital-based controls were recruited from family/internal medicine, thoracic and breast reduction surgery, and pulmonary, asthma, allergy, and dental clinics. Population-based controls were selected from Motor Vehicle Administration records. Inclusion criteria included being self-identified African-American or Caucasian and born in the United States. Subjects were excluded if they were HIV, HCV, or HBV carriers, were IV-drug users, were institutionalized, or were physically or mentally unable to sign a consent form and complete the questionnaire. Of the eligible subjects, 83% of the cases, 87% of the hospital-based controls with breast-reduction surgery, 92% of the other hospital controls, and 90% of the population-based controls, participated in the study. Tumor and blood samples were collected from cases, and blood samples from controls. None of the control subjects had a history of cancer. An interviewer-administered questionnaire evaluated the demographic, medical, reproductive, family, and occupational history of the subjects.